Process of preparing equilenin compounds and products of such process



Patented Oct. 31, 1950 UNITED STATES ENT ()FHCE PROCESS F PREPARINGEQUILENIN COMPQUNDS AND PRODUCTS OF SUCH PRGCESS N 0 Drawing.Application October 1, 19.46, Serial No. 700,380

28 Claims. 1

Our invention relates to the synthesis of steroids of the type in whichboth rings A and B are aromaticand especially to the synthesis ofequilenin and desoxyequilenin.

The complete synthesis involves five steps; which, however, except aswill be indicated, we believe to be individually new. The presentapplication describes all five steps, but its claims are directedspecifically to the fifth step and to the products obtained thereby; andthe first four steps form the subject-matter of four separateapplications respectively, which are filed as divisions of the presentapplication. The five steps of the complete synthesis are as follows:

a. l-keto-Y-R-1,2,3,4=-tetrahydrophenanthrene, in which R indicates asubstituent in the class consisting of hydrogen and lower-alkoxy groups(including lower-aralkoxy groups), desirably either hydrogen or themethoxy group, is condensed with a lower-alkyl formate, convenientlyethyl formate, in the presence of sodium methoxide, and desirably in aninert solvent, such as benzene for example; to produce1-ket0-2-hydroxymethylene 7 -R.-1,2,3,4-tetrahydrophenanthrene, asfollows:

1) H H H H H H H Eng}: H CHOH This product is new when R. is an alkoxyor aralkoxy group, but not when R is hydrogen.

1). l-keto 2 hydroxymethylene 7-R-l,2,3,4- tetrahydrophenanthrene istreated with hydroxylamine, desirably as the hydrochloride dissolved inacetic acid; to produce 10,11-dihydro- '7-R-phenanthro[2,l-dlisoxazole,as follows:

This product is new.

1,2,3,4-tetrahydrophenanthrene, which is commonly not isolated, and(second) 2-cyano-1- keto 7 R Z-methyl-1,2,3,4-tetrahydrophenanthrene, asfollows:

(3) H HR The products obtained by reactions 3 and 4 are new.

By treating the product of reaction 3 with a mineral acid, we can get amodification in which a hydrogen atom takes the place of the sodiumatom; and, if desired, that modified product, after being treated withsodium methoxide, may be used as the starting point for reaction 4.

d. The 2-cyano-l-keto-7-R- 2 -methyl-1,2,3,4- tetrahydrophenanthrene iscondensed with a dilower-alkyl succinate, preferably dimethyl succinate,in the presence of an alkali-metal tertiarylower-alkoxide, convenientlypotassium tertiarybutoxide; preferably followed by treatment with amineral acid, for instance hydrochloric acid; to produce a15-carboalkoxy 14,15 dehydroequilenin ether or15-carboalkoxy-14,15-dehydrodesoxyequilenin, according to whether R is aradical or hydrogen; and the product so obtained is hydrolyzed,desirably with barium hydroxide followed by hydrochloric acid, to givethe free acid,

H 0113 H GN cHlcoooHS nlcooona H01 irocwnm Bl H H o E V -000mm AA/ a oreH H 0 ex l H :c-cooo hydrolysis I) K H H 0 ax --CCOOH Ell The productsobtained by reactions 5 and 6 are new.

Reaction 6 is not only a hydrolysis of the carboalkoxy group at the 15position to a carboxy group, but a shifting of the double bond from the14-15 position to the 15-16 position. This shifting of the double bondis most surprising, and was not at first appreciated. No similarshifting, of the double bond has been observed in reaction 5. Theshifting of the double bond in reaction 6 may not be completelyquantitative, but it occurs in such large degree that no absence of ithas been observed in the reaction product.

c. This free acid, l5-carboxy-15,16-dehydroequilenin ether or15-carboxy-15,16-dehydrodesoxyequilenin, is decarboxylated by heatingunder reduced pressure; to produce a mixture of two isomericdehydroequilenin ethers or a mixture of two isomericdehydrodesoxyequilenins according to whether R. is a radical orhydrogen. The isomers or each pair diifer by having a double bond in the14,15-position on the one hand and in the 15,16-position on the other.This product, with or without separating its component isomers, ishydrogenated, desirably over a palladium-charcoal catalyst, to producetwo compounds, one of which is a racemic equilenin ether or a racemicidesoxycquilenin and the other of which is a racemic isoequilenin etherr a racemic desoxyis-oequilenin, in each case according to whether R isa radical or hydrogen. The two compounds so produced are stereoisomersin each case. These two compounds are separated, as by fractionalcrystallization. In the case where R is hydrogen, this separation givesdirectly d,l-desoxyequilenin and d,l-desoxyisoe uilenin. In the casewhere R is methoxy, the separated compounds are demethylated, by knownmethods, to obtain respectively d,l-equilenin and d,l-isoequilenin. Thed,l-equilenin is resolved, by known methods, to obtain d-equilenin,which is found to be identical with natural equilenin. The mainreactions involved are as follows:

7) CH3 CH3 H Double A I B bond in R R ring D The products of reaction 7are new.

(8) CH3 CH3 H H O H H O H\ V g H H Y C--H O D Pd=C J i A B Double H Hbond 1n demethylation R- ring D R when R is methoxy Reactions 6 and '7may be combined into a sin gle step which involves both hydrolysis as inreaction 6 and decarboxylation as in reaction 7, by treatment with amixture of a lower-aliphatic acid and a mineral acid, convenientlyacetic and hydrochloric acids; although in the event Where R is alkoxyor aralkoxy, it may he dealkylated to hydroxy. For example,l5-carboethoxy-l4,l5- dehydrodesoxyequilenin is treated with a mixtureof acetic and hydrochloric acids to give directly the mixture of twoisomeric dehydrodesoxyequilenins, as follows:

The following are examples of our process. The melting points given areall corrected for stem exposure.

EXAMPLE 1.-THE PREPARATION or EQUILENIN To a suspension of powderedsodium methoxide, (prepared by dissolving 3.39 g. of sodium in methanol,removing excess methanol by evaporation under reduced pressure, andheating at approximately 200 C. for one hour under high vacuum,) in cc.of dry benzene, is added 10.90 g. of ethyl formate; after which is addeda solution of 16.54 g. of 1-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene in cc. of benzene. The system containing themixture is evacuated; and then filled with nitrogen, and allowed tostand at room temperature for about 5 hours, with occasional swirling.A- copious yellow precipitate is formed. This precipitate is dissolvedby shaking with ether and ice water, and then allowing the whole toseparate into two layers. The water layer, which contains the 1-keto-7-methoxy 2 hydroxymethylene 1,2,3,4 tetrahydrophenanthrene in the form ofthe sodio derivative, is separated from the ether layer and preserved;and for complete recovery the ether layer is desirably washed thoroughlywith water and with dilute potassium hydroxide solution and the washingsadded to the separated aqueous layer. The combined aqueous solution isthen acidified, to cause separation of the l-keto-Z- hydroxymethylene 7methoxy l,2,3,4 tetrahydroxyphenanthrene, as yellow crystals. As firstobtained, these give a yield of about 17.73 g. (or 95%), melting atabout -13l.5 C.; which is of satisfactory purity for the next step. Thecrystals may be purified if desired, as by recrystallization severaltimes with alcohol; but the melting point is not materially changed,although somewhat sharpened, for the recrystallized crystals have amelting point of 130- 130.6 C.

Analysis shows the following: Calculated for CIGHMOBZ C, 75.57%; H,5.55%. Found; C', 75.37%; H, 5.68%.

The yellow crystalline l-keto-Z-hydroxymethylene 7 methoxy 1,2,3Atetrahydrophenanthrene thus obtained is used as the starting point forthe next step. The 17.73 g. of that hydroxymethylene ketone is dissolvedin about 400 cc. of glacial acetic acid, and the solution is stirredwith 7.25 g. of dry powdered hydroxylamine hydrochloride at about 68-70C. (the temperature of solution) for about 7 hours. The solution becomespink. The hot pink solution is diluted with about an equal volume of hotwater to the point of incipient cloudiness, and then allowed to cool;and on such cooling a deposit is obtained of usually colorless (althoughsometimes colored) crystals of 10,11-dihydro-7-methoxyphenanthro [2,1-d]isoxazole. The yield is about 15.81 g. (or about 90%), after drying at100-110 C. The melting point is about 137-138 (3., with softeningpreceding melting. Purification may be obtained by evaporativedistillation at C. at 0.5 to 1 mm. pressure, followed byrecrystallization from a mixture of methanol and ethyl acetate; whichgives colorless crystals melting at 139.5140 C.

Analysis shows the following: Calculated for C16H1302N: C, 76.47%; H,5.21%. Found: C, 76.71%; H, 5.07%.

The crude isoxazole may contain a small amount of a benzene-insolublematerial, possibly a phenolic product resulting from demethylation; butis nevertheless sufficiently pure for the next step.

The above procedure may be conveniently altered in the following way: Amixture of 16.87 g. of the crude 1-keto-2-hydroxymethylene-7- methoxyl,2,3,4 tetrahydrophenanthrene, 400 cc. of glacial acetic acid, and 6.91g. of hydroxylamine hydrochloride, is quickly heated to boiling Ether isadded, and

in an 011mm maintained at about 0'. The refluxing is then continued forabout 7 minutes, whereupon the solution (which is now red) is dilutedwith hot water until definitely turbid. The whole is then allowed tocool several hours in an ice box, during which time crystallization ofthe 10,11 dihydro 7 methoxyph-enanthro- [2,1-dlisoxazo1e occurs. Theisoxazole as thus obtained is in the form of tan-colored plates meltingat about 137-138 C., and the yield is about 15.80 g. (about 95%).

The next step may be either in two parts orin one part.

If it is in two parts, it is as follows:

First part To a cool solution of 0.9 g. of sodium in 11 cc. of methanolis added a filtered solution of 6.66 g. of the crude10,11-dihydro-7-methoxyphenanthro[2,1-dlisoxazole in 80 cc. of drybenzene. The mixture is stirred during the addition, which should takeabout 10 minutes, and then is stirred for about 3 hours longer, all atroom temperature.

successive portions of water liters in all). The water dissolves theproduct of the reaction, which is 2-cyano-l-keto.-7-,- methoxy 2 sodio1,2,3,4 tetrahydrophenanthrene and is sparingly water-soluble. The waterand ether layers are allowed to stand, so that they separate; and thewater layers are removed and preserved. For increased yield, the etherlayer is desirably extracted with dilute potassium hydroxide solution,and the extract is combinedwith the separated water layers. The combinedaqueous extract is then acidified, as with hydrochloric acid; and givesabout 6.23 g. (94% yield) of a yellow solid,2-cyano-l-keto-7-methoxyl2,3,4-tetrahydrophenanthrene, melting at about1634-1685 C. Although this is sufiiciently pure for the remainder of theprocess, it may be purified; as by vacuum sublimation, followed byrecrystallization from alcohol, to give, yellow plates melting at169.5-171 0. Analysis of the purified product shows the following:

Calculated for C1sH13O2N2 C, 76.47%; H, 5.21%. Found: C, 76.28%; H,5.38%.

Second part For this part, 6.00 g. of the crudeZ-cyanO-lketo-7-methoxy-l,2,3,4 tetrahydrophenanthrene and 30 cc. of drybenzene are added to a solution of 2.64 g. of sodium in 50 cc. ofmethanol; and the whole is refluxed for 15 minutes, with stirring. Themixture is cooled, 8 cc. of methyl iodide is added, and the stirring iscontinued at room temperature for about 45 minutes. Then an additional 8cc. of methyl iodide is added, and the stirring is continued untilsolution is practically complete, which usually takes about 2 or 3hours. The solution is then heated under reflux condi tions, for about 2hours, to complete the reaction; and a few drops of acetic acid areadded to neutralize the mixture, after which most of the solvent isremoved by evaporation in a current of air. Then about 100 cc. of wateris added; after which the product is extracted with a mixture of benzeneand ether, the organic layer is separated from the water layer, and thesolution thus obtained is successively washed thoroughly with water,several portions of dilute potassium hydroxide solution, and saturatedsalt solution. The benzene-ether solution is then dried over anhydrouspotassium carbonate; and then the solvent the mixture is shaken with;(desirably-about 1.5

is removed by evaporation to leave a solid residue; which iscrystallized from alcohol. This gives about 5.05 g. (an 80% yield) ofpale yellow crystals, melting at about 132.5-134.5 C. preceded by asoftening at about 130 C. This product, which is Z-cyano 1keto-7-methoxy-2-methyl-l,2,3,4- tetrahydrophenanthrene, is suflioientlypure for use for the remainder of the process. The yellow crystals maybe purified if desired, however, by evaporative distillation at 150 C.under a pressure of 0.5 to 1 mm., followed by recrystallization fromethyl acetate; which gives colorless needles melting at 135-1375 C.Analysis of the purified product shows the following: Calculated forC17H1502N2 C, 76.96%; H, 5.70%. Found: C, 77.10%; H, 5.90%.

If it is desired to produce the 2-cyano-1-keto- 7 -methoXy-2-methyl-1,234 tetrahydrophenanthrene in one step from the 10,11-dihydro-7-methoxyphenanthro[2,1-dlisoxazole, it may be done by direct methylationas follows:

To a cool solution of sodium methylate, formed by dissolving 7.5 g. ofsodium in 65 cc. of methanol is added, with stirring, a solution of 10.0g. of the crude isoxazole in 100 cc. of dry benzene. The addition ismade slowly, so that it takes about 20 minutes. The sodio derivative ofthe desired cyano compound is formed, as indicated by the appearance ofa yellow precipitate. The mixture is then stirred at room temperaturefor about 45 minutes. Then 15 cc. of methyl iodide is added, without anypreliminary separation, and the mixture is stirred for about 1 hour; andthen 10 cc. of methyl iodide is introduced, and the stirring iscontinued for about one-half hour. Then cc. of methyl iodide is added,and the whole is refluxed for about 2% hours, and the solution is workedup as described in the preceding two-step process following the additionof the methyl iodide. In this one-step method, the 2-cyano-1-keto-7-methoxy-2 methyl 1,2,3,4 tetrahydro phenanthrene is obtaineddirectly as almost colorless crystals, melting at about 135-137 C., witha yield of about 9.25 g., or about 88% of the theoretical amount.

A second crop of crystals may if desired be obtained from the motherliquor. These crystals are undoubtedly a mixture, melting at about 100-120 C., and we are not sure what they are.

The 2-cyano 1 keto 7 methoxy-Z-methyl- 1 2 3 4 tetrahydrophenanthrene,whether obtained by the two-step or the one-step process, may be used asthe starting point for the next step, to produce a 15 carboallroxy 14,15dehydroequilenin methyl ether. evidence of a shifting in the position ofthe double bond in ring D at this stage.

The 15-carboethoxy compound is prepared as follows:

A solution is made of 1.08 g. of potassium in cc. of tertiary-butylalcohol. The system containing the solution is evacuated of air andfilled with nitrogen, and then there are successively added (a) 6.8 cc.of diethyl succinate, and (b) 3.30 g. of the crude2-cyano-l-lreto-7-methoxy-2- methyl 12,3,4 tetrahydrophenanthrene; whichlatter is conveniently transferred with the aid of an additional cc. oftertiary-bitty] alcohol. The system is desirably again evacuated, andrefilled with nitrogen. Then the mixture is heated in an oil bathmaintained at 50-55 C. for about 7 hours; with suitable stirring (suchas magnetic stirring) which will not interfere with the maintenance ofthe system under nitrogen. Then the mixture is cooled, and poured intoexcess dilute We have not seen any hydrochloric acid; after which thetertiary-butyl alcohol is removed by evaporation at reduced pressure,leaving a solid organic residue. A small amount of water is added, andthen that solid organic residue is taken up in a mixture of benzene andether, and the water and benzene-ether layers are allowed to separate onstanding and the water layer is discarded; and the benzene-ether layeris washed successively with dilute hydrochloric acid, water, two cc.portions of 5% p0- tassium hydroxide solution (which removes some butvery little acidic material), once again with water, and finally withsaturated salt solution. The thus-washed benzene solution is dried overanhydrous sodium sulfate, and concentrated by evaporation to a smallvolume. Then methanol is added, which causes the desired 15carboethoxy-14,15-dehydroequilenin methyl ether to crystallize in theform of pale yellow fiufiy needles, which melt at about 179-183 C.,after some preliminary softening at about 176 C. The yield is about 2.27g. or about 52%. This methyl ether is of sufficient purity for thesucceeding step in the synthesis. It may be purified, however, ifdesired, by recrystallizing from benzene-methanol, and subliming at 160C. under a pressure of 0.5 to 1 mm., followed by recrystallization fromethyl acetate. This yields colorless felted needles melting at183.6-1842" C. Analysis of the purified product shows: Calculated for0221-12204: C, 75.41%; H, 6.33%. Found: C, 75.64%; H, 6.47%.

The lS-carbomethoxy compound is prepared as follows:

A three-neck flask is fitted With a dropping funnel and a gas-tightstirrer (to enable evacuation of the system). The third neck of theflask is connected by pressure tubing to the top of the dropping funneland to a three-way stop-cock, which will enable evacuation and admissionof nitrogen gas.

In the funnel is placed a solution of 4.0 g. of potassium in 100 cc. ofpure, dry tertiary-butyl alcohol; and 15 cc. of dimethyl succinate isthen mixed with this solution. In the flask is placed 4.00 g. of crude,dry 2-cyano-1keto-7-methoxy- 2 methyl 12,3,4-tetrahydrophenanthrene, andthe whole system is evacuated and filled with nitrogen. About 20 cc. ofthe solution in the funnel is then admitted to the flask. The mixture isthen slowly stirred for 1 hour while the flask is heated in an oil bathmaintained at about 53 C.; during which time the color develops fromalmost colorless to orange. The remaining contents of the funnel is nowadded dropwise, at such a rate that addition is complete after about 4hours, and the stirring and heating are continued as before during thisperiod and for about 1 more hour after the addition is complete. Thereaction mixture, which has now become bright yellow and pasty, is thencooled, and treated with 100 cc. of 5N hydrochloric acid; which gives aclear orange solution. The tertiary-butyl alcohol is removed in acurrent of nitrogen, water is added, and the suspension of yellow solidis extracted twice with benzene and the two benzene extracts combined.The combined benzene solution is washed with dilute hydrochloric acid,with water, with dilute potassium hydroxide solution, and finallyseveral times with water. The benzene is then evaporated, as on a steambath, in a current of nitrogen; which leaves a light yellow solid. Thisis triturated with petroleum ether, after which there remains about 4.06g. (an yield) of light yellow crystalline l5carbomethoxy-14,15-dehydroequilenin methyl ether melting at about164-167" C.

9 This methyl ether is of satisfactory purity for the next step; but itmay be further purified, if desired, by recrystallization from methanol,which finally gives colorless plates melting'at 170-17 1 C.

The analysis shows: Calculated for C21H20O4: C, 74.98% H, 5.99%. Found:C, 74.72%; H, 6.04%.

The 15 carbo-tertiary-butoxy-14,15-dehydroequilenin methyl ether isprepared as follows: To a solution of 0.16 g. of potassium in 6 cc. ofdry tertiary-butyl alcohol is added a solution of 1.4 g. ofdi-tertiary-butyl succinate in cc. of dry benzene. To this mixture isthen added a solution of 0.500 of crude Z-cyano-1-keto-7-mthoxy-2-methyl-12,3,4-tetrahydrophenanthrene in cc. of dry benzene, and thewhole system is evacuated and filled with nitrogen. The benzenesolution, which becomes red, is refluxed for 1% hours; and

is then treated with dilute hydrochloric acid as.

described in the procedure for making the 15- carbomethoxy product. Thedesired final 15- carbo-tertiary-butyl product is obtained in crude formby evaporation of the benzene, and is an orange-red oil; which isdissolved in 15 cc. of hot methanol and allowed to crystallize. Theyield is about 0.094 g. (or 13% of red plates melting at about 177-187C. Purification may be obtained by sublimation at high vacuum andrecrystallization from methanol. As thus obtained it is in the form ofcolorless needles melting at 191.5-193 C.

The analysis shows: Calculated for Call-T2604: C, 76.16%; H, 6.93%.Found: C, 75.60%; H, 6.97%.

Any of these 1.5-carboalkoxy-14,15-dehydroequilenin methyl ethers may behydrolyzed to it convert the carboalkoxy group at the 15 position to acarboxy group; and during this hydrolysis a surprising shifting of thedouble bond in rin D occurs, from the 14-15 position to the 15-16position, to make the reaction product a 15-carboxy-15,16-dehydroequilenin methyl ether. For instance, a mixture of 2.27 g.of the crude l5-carboethoxy-14,15-dehyclroequilenin ether obtained asabove, and 2.27 g. of barium hydroxide octah'ydrate in 26 cc. of waterand 34 cc. of alcohol, is boiled under reflux conditions in anatmosphere of nitrogen for one hour. This makes a pink solution, whichis concentrated under reduced pressure until crystallization begins;which crystallization is of the sparingly soluble barium salt of the15-carboxy compound. The solution is cooled, and the barium salt isrecovered by filtration and washed with water. The filtrate stillcontains a small amount of the barium salt; which can be recovered asthe 15-carboxy acid by acidification of that filtrate, a withhydrochloric acid. The solidified barium salt may be converted into thel5-carboxy acid by warming it with about 350 cc. of dilute hydrochloricacid. This acid is the desired 15-carboxy-l5,16dehydroequilenin methylether; and after being Washed with water it melts at about 194-195 C.with decomposition, preceded by some softening at about 185 C. This15-carboxy-15,16-dehydro product, which is obtained in almostquantitative yield from the 15-carboethoxy-14,15-dehydro compound, issatisfactory for the next step of the synthesis. It may be purifiedsomewhat, however, by being recrystallized three times from benzene anddried at -60 C. at about 5 mm. pressure for about 20 hours; which givespale yellow crystals melting at 196.5-197.5 C. with decompo sition. Theanalysis shows: Calculated for czoHisOlt C, 74.52%; H, 5.63%. Found: C,75.01%; H, 5.49%.

doubtedly a mixture.

iii

The hydrolysis may also be efiected by an alternative procedure; whichfor the 15-carbomethoxy-14,l5-dehydro compound is as follows:

To a suspension of 4.06 g. of the crude15-carbomethoxy-14,15-dehydroequilenin methyl ether in 46 cc. of waterand cc. of alcohol is added 4.06 g. of barium hydroxide octahydrate. Thesystem is evacuated and filled with nitrogen, and is then refluxed forone hour. The pink solution is concentrated under reduced pressure untilprecipitation is obtained of the relatively insoluble barium salt of the15-carboxy-15,-16-dehydro acid. The whole is then cooled, and mixed withabout 600 cc. of about 6N hydrochloric acid, and the mixture is thenheated on the steam bath for about 1 /2 hours, to convert the bariumsalt into the 15.-carboxy-15,16-dehydro acid; which is an orangecrystalline product. This is separated by filtration, and without dryingis recrystallized from benzene; which gives about 3.77 'g. (a 97% yield)of light orange crystals of 15-carboxy- 15,16-dehydroequilenin methylether, melting at about 194.5-196.5 C. It is desirable to dry the finalproduct overnight at 100 in order completely to remove the benzene.

The 15-carboxy-15,16-dehydroequilenin methyl ether is nowdecarboxylated. To this end, 1.90 g. of it is placed in the bottom of asubliming tube, and covered with a tightly fitting wad of pyrex glasswool. The tube is then evacuated to below residual pressure, of theorder or 20 to 25 mm., and heated to about 200 C. for about minutes.Carbon dioxide is evolved, at first steadily but slackening ofi" slowlyas the end of the heating period is approached. As the evolution ofcarbon dioxide drops off, some colorless oil condenses in the cool partof the sublimi'n'g tube. Thereuponthe pressure is drastically loweredfurther, to less than 0.5 mm., and the heating is continued for about 1/2 hours longer. During this time a colorless, partly crystallinesublimate collects in the cool part of the tube. V

This sublimate is washed out of the tube with acetone. The acetonesolution is concentrated,

* methanol is added, and the solution is further concentrated untilcrystals form; whereuponthe whole is cooled. On this cooling, about0.595 g. of 14,15-dehydroequilenin methyl ether separates out ascolorless plates, melting at about 153-4585 0. with preliminarysoftening. Purification may be obtained by subliming at about 140 atabout 0.5 mm. pressure, followed b recrystallization from a mixture ofacetone and methanol; which produces crystals melting at 161.5-162.5 C.The analysis shows: Calculated for ClQHlBOZI C, 81.99%; H, 6.52%. Found:C, 82.01%; H, 6.36%.

A. second crop of crystals may be obtained by concentration of theoriginal mother liquor. This second crop melts at about 100 C.; and isun- The mixture contains an isomeric dehydroequilenin methyl ether, the15,16-dehydroequilenin methyl ether The 14,15-dehydroe'quilenin methylether, of the first crop of crystals, may be hydrogenated at the doublebond, catalytically. A solution of 0.604 g. of sublimed andrecrystallized 14,15-dehydroequilenin methyl ether in 50 cc. of ethylacetate is mixed with 0.150 g. of 30% palladiumcharcoal catalyst, andthe whole is stirred in an atmosphere of hydrogen, conveniently withmagnetic stirring. The hydrogen is gradually absorbed-the volumecalculated for the complete hydrogenation at the 14,15 double bond beintaken up in about '30 minutes. Then the catalyst i removed, as bysuitable filtration, and the ethyl acetate is removed by evaporation ina current of air; which leaves a colorless residue,

which is crystallized from a mixture of acetone and methanol. The firstcrop of crystals (0.407 g.) is separated in the form of perfectdiamondshaped plates, melting at about 185-189 C. with preliminarysoftening at about 183 C. This is racemic equilenin methyl ether. It maybe recrystallized. After recrystallization twice from a mixture ofacetone and methanol it melts at 189 190.5 C. This corresponds closelywith the melting point reported by Bachmann, Cole and Wilds for the samecompound produced in a different manner. See Journal of the AmericanChemical Society, vol. 62, page 824 et seq., published in 1940.

From the mother liquor we can obtain a second crop of crystals-about0.163 g. of colorless prisms which melt at about l27-l30 C. This productis largely racemic isoequilenin methyl ether. Recrystallization raisesthe melting point to about 129-l30 C.; which agrees with the valuereported by Bachmann, Cole and Wilds.

The yields of the two isomeric compounds, racemic equilenin methyl etherand racemic isoequilenin methyl ether, are about 67% and 27%respectively; making th total yield for the reduction about 94% Theracemic equilenin methyl ether may be demethylated and resolved in aknown manner, giving natural equilem'n.

EXAMPLE 2.THE PREPARATION or DESOXYEQUILENIN To a suspension of powderedsodium methoxide (prepared by dissolving 1.28 g. of sodium in methanol,removing the excess methanol by evaporation under reduced pressure, andheating at approximately 200 C. for 1 hour under high vacuum), in 100cc. of dry benzene, is added 4.12 g. of ethyl formate; after which isadded a solution of 5.40 g. of l-keto-l,2,3,4-tetrahydrophenanthrene in50 cc. of benzene. The system containing the mixture is evacuated, andthen filled with nitrogen and allowed to stand at room temperature forabout four hours, with occasional swirling. During this time the mixturevery slowly assumes a slight pink tinge and gradually becomes veryviscous. Cold water is then added, followed by a small amount of etherto minimize formation of emulsions, and the whole is shaken Well andthen allowed to separate into two layers. The water layer, whichcontains 1keto-2- hydroxymethylene 1,2,3,4 tetrahydrophenanthrene in theform of its sodio derivative, is separated from the ether layer andpreserved; and for complete recovery the ether layer is desirably washedthoroughly with water and with dilute potassium hydroxide solution andthe washings added to the separated aqueous layer. The combined aqueoussolution is then acidified, to cause the separation of thel-keto-2-hydroxymethylene-1,2,3,4-tetrahydrophenanthrene, as alightyellow solid. The yield of this product is about 5.82 g. (or 94%),and the melting point is about 82-83 C. This corresponds fairly closelywith the melting point reported by Meyer and Reichstein for the samecompound produced by a different procedure. See Pharmaceutical ActaHelvetiae, vol. 19, page 128 et seq., published in 1944.

The 1-keto-2-hydroxymethylene-1,2,3,4-tetrahydrophenanthrene thusobtained is used as the starting point for the next step: 21.5 g. ofhydroxymethylene ketone is dissolved in about 41.

III

cc. of glacial acetic acid, and the solution is stirred with 9.75 g. ofdry powdered hydroxylamine hydrochloride at about C. for about 6 hours.Sufiicient crushed ice is then added to bring the volume of solution toabout 2 liters. When the ice has melted, there is present a light pinksolid, which is filtered OE and dried in an oven at about 60 C. Thissolid is 10,11-dihydrophenanthro[2,l-dlisoxazole; it amounts to about 20g. (a 94% yield), and has a melting point of about 104-107 C. Thismaterial is of satisfactory purity for the next step in the synthesis.Purification may be obtained if desired, by recrystallization fromdilute alcohol; which gives colorless crystals melting at l09.8-110.5 C,

Analysis shows the following: Calculated for C15l-I11ON: C, 81.42%; H,5.01%; N, 6.33%. Found: C, 81.71% H, 4.90% N, 6.48%.

The next step may be either in two parts or in one part.

If it is in two parts, it is as follows:

First part To a cool solution of 3.2 g. of sodium in 40 cc. of methanolis added a solution of 20 g. of crude10,11-dihydrophenanthro[2,1-dlisoxazole in 250 cc. of dry benzene. Ayellow precipitate of 2-cyano-l-keto-2-sodio 1,2,3,4tetrahydrophenanthrene separates as the solution is allowed to stand atroom temperature for about 30 minutes. Ether is added, and the mixtureis shaken with about 1 liter of water. The water and ether layers areallowed to stand, so that they separate; and the water layer is removedand preserved. In order to recover more material from the ether layer,it is washed with successiv portions of dilute sodium hydroxide(desirably a total of about 4 liters), and these washings are allcombined with the aqueous extract and then acidified, as withhydrochloric acid. This gives about 18.8 g. (a yield) of light tanZ-cyano-l-keto- 1,2,3,4-tetrahydrophenanthrene, melting at about125-1265 C. Although this is sufliciently pure for the remainder of theprocess, it may be purifled by recrystallization from dilute alcohol,which gives colorless plates melting at 128-l29 C.

The analysis shows: Calculated for CrsI-IuON: C, 81.42%; H. 5.01%; N,6.33%. Found: C, 81.68%; H, 4.96%; N, 6.39%.

Second part For the next step, 18.8 g. of the crude 2-cyano-1-keto-12,3,4-tetrahydrophenanthrene dissolved in 67 cc. of warm benzeneis added to a solution of 7.3 g. of sodium in cc. of methanol; and thewhole is refluxed for 15 minutes, with stirring. The mixture is cooled,11 cc. of methyl iodide is added, and the stirring is continued at roomtemperature for about 45 minutes. Then an additional 11 cc. of methyliodide is added, and the solution is allowed to stand for about 30minutes. Finally 5 cc. more of methyl iodide is added, and the solutionis refluxed for 1% hours to complete the reaction. The solvents are thenremoved under reduced pressure, and th residue is dissolved in benzeneand is washed thoroughly with several portions of dilute potassiumhydroxide solution. The benzene solution is then dried over anhydrouspotassium carbonate; and the solvent is removed by evaporation to leavea solid residue, which is crystallized from methanol. This gives a totalof about 16.7 g. (a yield of 83%) of material melting at about 121-127"C. This product is Z-cyano-1-ket0-2-methyl-1,2,3,4tetrahydrophenanthrene, and is sufiiciently pure for use for theremainder of the process. The materialmay be purified if desired,however, by recrystallization from methanol; which gives colorlessplates melting at 126-127 C. Analysis of the purified product shows thefollowing: Calculated for CmHIsON! C, 81.67%; H, 5.57%. Found: C,81.70%; H, 5.58%.

If it is desired to produce the 2-cyano-1-keto-Z-methyl-12,3,4-tetrahydrophenanthrene in one step from the10,11-dihydrophenanthro[2,1-dl isoxazole, it may be done by directmethylation as follows:

To a cool solution of 0.6 g. of sodium in 28 cc. of methanol is added asolution of 4.7 g. ofthe crude isoxazole in 17 cc. of benzene. Thissolution is allowed to stand for 30 minutes at room temperature, and isthen refluxed for lO-minutes and cooled. To this cool solution is nowadded 3 cc. of methyl iodide; and the mixture is shaken, and thenallowed to stand at room temperature for 1 hour. A second portion (2cc.) of methyl iodide is then added, and the solution is allowed tostand for 2 hours at room temperature, and then is refluxed for 4 hours.The reaction mixture is worked up as described in the preceding 2-stepprocess following the addition of the methyl iodide. In this l-stepmethod, the 2-cyano -1- keto 2 methyl-1,2,3,4-tetrahydrophenanthrene isobtained directly in about 91% yield. The weight is about 4.55 g. andthe melting point is about 124.5 -126 C.

The 2-cyano-1-keto-2-rnethyl-l,2,3,4-tetrahydrophenanthrene, whetherobtained by the 2-step process or the 1-step process, may be used as thestarting point for the next step, to produce -carboethoxy 14,15dehydrodesoxyequilenin. This is done as follows:

To a cool solution of 0.74 g. of potassium dissolved in cc. of drytertiary-butyl alcohol is added 6.6 cc. of diethyl succinate, followedby 2.00 g. of crude2-cyano-1-keto-2-methyl-1,2,3,ltetrahydrophenanthrene. The systemcontaining the solution is evacuated, filled with nitrogen, and thenstoppered and shaken mechanically for 7 hours. After the first 3 hoursnearly all of the solid material is in solution and the reaction mixtureis deep red; by the end of the shaking period, however, a light yellowprecipitate has formed. An excess of dilute hydrochloric acid is addedto the mixture, and most of the solvent is then removed under reducedpressure. A small amount of water is added, then the organic residue istaken up in a mixture of benzene and ether, and

the water and benzene-ether layers are allowed to separate on standingand the water layer is discarded; and the benzene-ether layer is washedsuccessively with dilute hydrochloric acid, water, three portions ofdilute potassium hydroxide solution, once again with water, and finallywith saturated salt solution. The thus-washed benzene solution is driedover anhydrous sodium sulphate and concentrated to a small volume underreduced pressure, to leave a residual light red oil. This is dilutedwith hot methanol. 15- Carboethoxy-14,l5-dehydrodesoxyequilenin slowlycrystallizes out as the solution cools, as a light pink product; whichamounts to about 1.50 g., and melts at about 151-1585 C. This1-5-carboethoxy-14,15-dehydro material is of sufiicient purity for thenext step in the synthesis. The

product may be purified, however, if desired, by

recrystallization from methanol; which gives faintly pink crystalsmelting at 152.5-153.5 C.

The analysis shows: Calculated for CzlHzoGs:

14 C, 78.74% H, 6.29%. Found: C, 78.55%, 78.49% H, 6.23%, 6.22%.

The 15-carboethoxy-14,15-dehydrodesoxyequilenin now hydrolyzed, inalmost quantitative yield, to 15 carboxy 15,16 dehydrodesoxyequilenin;which involves not only a conversion of the carboethoxy group at the15-position to a carboXy group, but a shifting of the double bondin ringD from the 14-15 position to the 15-16 position. To do this a mixture of1.00 g. of the crude 15-carboethoxy-14,15-dehydro compound justobtained, and 1.00 g. of barium hydroxide octahydrate in 25 cc. ofalcohol, is boiled under reflux conditions in an atmosphere of nitrogenfor 1 hours. The resulting solution is concentrated under reducedpressure, and the residue is acidified with excess dilute hydrochloricacid; which effects the precipitation ofan oil. This oil is extractedwith ether, and the ether solution is in turn extracted with a saturatedsolution of sodium bicarbonate. Acidification of the sodium bicarbonateextract, as by hydrochloric acid, gives about 0.88 g. (a 97% yield) oflight yellow crystals 0f'15-carb0xy-15J6- dehydrodesoxyequilenin, whichmelts at about 228231 C. with decomposition. This 15-carboxy acid may bepurified, if desired, by recrystallization from alcohol.

The analysisshows: Calculated for CisHwOaJC, 78.06%; H, 5.52%. Found: C,77.76%; H, 5.44%.

The 14,15- and l5,16-dehydrodesoxyequilenins may be prepared bydecarboxylation of this 15- carbox-y-15,16-dehydrodesoxyequilenin; inthe same manner that the 14,15- and 15,16-dehydroequilenin methyl etherswere prepared in Example 1 by decarboxylation of.15.-carboXy-15,16-dehydroequilenin methyl ether. But it is alsoconvenient to prepare them directly froml5-carboethoxy-14,15-dehydrodesoxyequilenin. This is accomplished asfollows:

A mixture of 2.00 g. of the. crude15-carboethoXy-14,15-dehydrodesoxyequilenin, 25 cc. of acetic acid, 18.5cc. of water, and 12.5 cc. of concentrated hydrochloric acid, isrefluxed for 10 /2 hours in an atmosphere of nitrogen. The solu- 5 tionis then concentrated under reduced pressure,

to leave a light red oil; which is taken up in ether. The ether solutionis washed twice with dilute potassium hydroxide solution. once withdilute hydrochloric acid, and finally with satu rated salt solution;after which the ether is removed by evaporation, and the now red-orangeresidual oil is evaporatively distilled at reduced pressure. Thedistillate consists of an almost colorless partly crystalline oil, andthis product is crystallized from alcoholto give a total of about 0.55g. of 14,15-dehydrodesoxyequilenin in the form of colorless needlesmelting at about 134- 136 C. This product may be purified by sublimationat r duced pressure and recrystallization from alcohol, to give materialmelting at 136.8- 138 C.

The analysis shows: Calculated for C18HlGO Z C, 87.06%; H, 6.50%. Found:C, 86.81%; H, 6.21%.

The original mother liquor is evaporat d to dryness, to leave acrystalline residue, which after recrystallization from a mixture ofether and petroleum ether amounts to about 0.62 g. of tan cubicalcrystals which melt at about -102 C. This product is15,16-dehydrodesoxyequilenin; it may be purified by sublimation underreduced pressure and recrystallization from a mixture of ether andpetroleum ether to givecclorless crystals melting at 100.5402 C.

The analysis shows Calculated for 018E: C, 87.06%; H, 6.50%. Found: C,87.05%; H, 6.46%.

The 14,l-dehydrodesoxyequilenin may be hydrogenated at the double bond,catalytically. In order to do this, a solution of 260 mg. of thepurified unsaturated 14,15-dehydrodesoxyequilenin, in cc. of ethylacetate, is mixed with 50 mg. of palladium-charcoal catalyst, and thewhole is stirred in an atmosphere of hydrogen, conveniently withmagnetic stirring. The hydrogen is gradually absorbedthe volumecalculated for the hydrogenation of the 14,15- double bond being takenup in about 2 hours. The catalyst is removed by filtration, and thesolution is evaporated, leaving a while solid; which is recrystallizedas white flakes from a mixture of acetone and ethyl alcohol. These whiteflakes are desoxyequilenin, of a total weight of about 165 mg.; and meltat about 183-188" C. in an evacuated tube. When this product isrecrystallized the melting point is raised to l89-l91 C. (in anevacuated tube). with the melting point reported by Bachmann and Wildsfor the same compound (called by them fi-l'I-equilenone) produced in adifferent man ner. See Journal of the American Chemical Society, vol.62, page 2084, et seq., published in 1940.

The 15,16-dehydrodesoxyequilenin may be hydrogenated according to theprocedure de scribed above for the 14,15-isomer. The hydrogenation iscomplete in about 1 /2 hours, and a total of about 196 mg. of colorlesscrystals is obtained by crystallization from a mixture of methanol andacetone. This product is desoxyisoequilenin, and melts at 100-102 C.This corresponds closely with the melting point reported by Bachmann andWilds for the same compound (called by them a-l'l-equilenone) producedin a different manner.

We claim as our invention:

1. The process of producing dehydroequilenin ethers, in which the ethergroup is a lower-alkoxy group, which consists in decarboxylating a 15-carboxy-l5,lfi-dehydroequilenin ether by heat.

2. A dehydroequilenin ether, in which the ether group is a lower-alkoxygroup, and in which a double bond is at one of the 14,15 and 15,16positions.

3. 14,15-dehydroequilenin methyl ether.

4. 5,16-dehydroequilenin methyl ether.

5. The process of producing dehydrodesoxyequilenins, which consists indecarlooxylating 15- carboxy-15,16-dehydrodesoxyequilenin by heating itunder reduced pressure.

6. A dehydrodesoxyequilenin having a double bond in one of the 14,15 and15,16 positions.

7. 14,l5-dehydrodesoxyequilenin.

8. 15,16-clehydrodesoxyequilenin.

9. The process of producing a dehydrodesoxyequilenin from a15-carboalkoxy-14,15-dehydrodesoxyequilenin, which consists in heatingthe latter in a mixture of a lower aliphatic acid and a mineral acid.

10. The process as set forth in claim 9, in which the lower aliphaticacid is acetic acid.

11. The process as setforth in claim 9, in which the mineral acid ishydrochloric acid.

12. The process for substituting a hydrogen atom for the carboalkoxygroup of a 15-carboalkoxy-li,15-dehydroequilenin ether, in which theether group is a lower-alkoxy group, which consists in heating thelfi-carboalkoxy compound in a mixture of a lower aliphatic acid and amineral acid.

13. The process of producing a racemic equilenin ether, in which theether group is a lower- This corresponds closely alkoxy group, whichconsists in hydrogenating a dehydroequilenin ether.

14. The process as set forth in claim 13 in which the hydrogenation isdone over a palladium-charcoal catalyst.

15. The process of producing a racemic desoxyequilenin, which consistsin hydrogenating a dehydrodesoxyequilenin.

16. The process as set forth in claim 15, in which the hydrogenation isdone over a palladium-charcoal catalyst.

17. The process of producing desoxyequilenin, which consists inhydrogenating 14,15-dehydrodesoxyequilenin.

18. The process as set forth in claim 17, in which the hydrogenation isdone over a palladium-charcoal catalyst.

19. The process of producing desoxyisoequilenin, which consists inhydrogenating 15,16-dehydrodesoxyequilenin.

20. The process as set forth in claim 19, in which the hydrogenation isdone over a palladium-charcoal catalyst.

21. The process of producing a dehydroequilenin compound represented bythe following formula:

A t inringD HHO vn ,a Double bond in ring D COOK .All

in which R has the same meaning as before, and R is a member of theclass consisting of hydrogen and lower-alkyl groups.

22. A dehydroequilenin compound having the following formula:

Double bond in ring D in which R represents a member of the classconsisting of hydrogen and lower-alkoxy groups, and there is in ring D adouble bond extending between the 15 position and an adjacent position.

23. The process of producing an equilenin compound represented by thefollowing formula:

in which R represents a member of the class consisting of hydrogen andlower-alkoxy groups, which consists in hydrogenating a correspondingequilenin compound having in ring D a double bond extending between the15 position and one of the adjacent positions.

24. The process of producing an equilenin compound represented by thefollowing formula:

in which R represents a member of the class consisting of hydrogen andlower-alkoxy groups,

WILLIAM s. JOHNSON. JACK W. PETERSEN. CARL DAVID GUTSCHE.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,677,086 Herz July 10, 19281,754,031 Mayer Apr. 8, 1930 2,115,681 Hofier Apr. 26, 1938 2,368,204.-Dannenbaum Jan. 30, 1945 2,&18,603

Schwenk Apr. 8, 1947 fiertificate of Correction Patent No. 2,527,999October 31, 1950 WILLIAM S. J OHNSGN ET AL.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as follows:

Column 4, lines 28 to 30, for that portion of the equation readingcolumn 11, line 7 4, after the Word of insert that; column 14, line 4,before now insert is column 15, line 49, for 5, 16 read 15, 16;

and that the said Letters Patent should be read as corrected above, sothat the same may conform to the record of the case in the PatentOffice.

Signed and sealed this 20th day of February, A. D. 1951.

THOMAS F. MURPHY,

Assistant Commissioner of Patents.

1. THE PROCESS OF PRODUCING DEHYDROEQUILENIN ETHERS, IN WHICH THE ETHERGROUP IS A LOWER-ALKOXY GROUP, WHICH CONSISTS IN DECARBOXYLATING A15CARBOXY-15,16-DEHYDROEQUILENIN ETHER BY HEAT.